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Background/Objectives: To investigate prevalence, healthcare utilization, and comorbidities of patients with TS who were hospitalized in the United States.
Methods: Patients with TS were identified within the Nationwide Inpatient Sample (NIS) database from the year 2017 to 2019 using ICD-9 diagnostic code. This database collected data from over 4000 hospitals across the US. Data on patient and hospital characteristics, morbidities, mortality and expenditures were retrieved. A propensity-matched cohort of non-TS patients from the same database was constructed to serve as comparators.
Results: We identified 9,845 TS patients, corresponding to inpatient prevalence of 10.4 per 100,000 admissions. The most common reason for hospitalization was sepsis (28%). Compared to the comparators, TS patients had higher inpatient mortality (adjusted odds ratio [aOR] 2.16 (95% CI 1.57- 2.96) and various morbidities such as shock (aOR 1.68, 95% CI 1.30- 2.17), ICU admission (aOR 1.31, 95% CI 1.10- 1.55), and multi-organ failure (aOR 1.34, 95% CI 1.17- 1.54). They also had significantly higher odds of several comorbidities such as stroke, myocardial infarction, and autoimmune diseases. After adjusting for confounders, TS patients had longer length of stay (5.1 days vs. 4.5 days, p < 0.01) and displayed a mean additional $5,382 (p < 0.01) in total hospital costs and a mean additional $20,083 (p < 0.01) in total hospitalization charges when compared to non-TS patients.
Conclusion: Hospitalization of patients with TS was associated with a significantly higher morbidity, mortality, and expenditures compared to non-TS patients. Patients with TS have a higher risk of cardiovascular complications and autoimmune diseases.
References:
Grants: Not applicable.
Conflict of Interest: Jirat Chenbhanich University Hospitals/Case Western Reserve University, Patompong Ungprasert Cleveland Clinic, OH, Paul Kroner Mayo Clinic, FL.
EP12.002 Mutational characterization of the CORO2B gene and its relationship to ciliopathies Carlos López Solarat 1;2, Diana Valverde Pérez1;2 1Centro De Investigaciones Biomédicas (CINBIO), Vigo, Spain; 2Instituto de Investigación Sanitaria Galicia Sur, Vigo, SpainBackground/Objectives: The CORO2B gene belongs to the family of actin-binding coronin proteins involved in cellular processes such as cell division, cell migration and movement, vesicle trafficking within the cytosol and phagocytosis These processes are often altered in ciliopathies, one of them is Bardet Biedl syndrome (BBS MIM# 209900), a multisystem disease whose main symptoms are retinal degeneration, obesity, polydactyly, mental retardation, cryptorchidism and defects in renal structure and function. This high genetic heterogeneity cannot fully explain the large inter- and intra-familial phenotypic variability when members of the same family carry the same causal variant(s), suggesting that other mechanisms are involved in the development of the phenotype.
Methods: Exome sequencing of two patients with clinical suspicion of BBS, subsequent validation by Sanger sequencing. Functional analyses were composed of confocal microscopy of the CORO2B subcellular localization and quantification of expression levels. Immunoprecipitation and cofactor proteomics are currently undergoing.
Results: We describe two new mutations in the CORO2B gene placing it as a possible candidate to modulate the BBS phenotype. In the present work we functionally characterize a set of 3 mutations (Ala 129 Val, Leu 194 Gln and Pro 318 Leu), two found by sequencing and one more extracted from VarSome.
Conclusion: We identified novel the mutations Ala 129 Val, Leu 194 Gln and Pro 318 Leu in the CORO2B gene in two BBS patients. Functional analyses indicate that Ala 129 Val and Pro 318 Leu could have a pathogenic character.
References:
Grants:
Conflict of Interest: None declared.
EP12.003 A case of structural brain anomalies with impaired intellectual development and craniosynostosis caused by a novel ZIC1 gene variant Trayan Delchev 1, Tsvetina Veleva1, Maria Sredkova-Ruskova1, Daniela Avdjieva-Tzavella1 1University Children Hospital, Clinical Geneitcs, Sofia, BulgariaBackground/Objectives: Structural brain anomalies with impaired intellectual development and craniosynostosis (BAIDCS) is an extremely rare autosomal dominant condition caused by certain mutations in the ZIC1 (Zic Family Member 1) gene. It encodes a member of the ZIC family of C2H2-type zinc finger proteins which are important during development.
We present a seven-month-old boy, born small for gestational age, with uneventful neonatal period. Due to severe dysmorphic features (turricephalic head shape, facial asymmetry, mild ocular proptosis, hypertelorism, tented upper lip, low set ears, short neck, and broad thumbs) along with psychomotor delay, the child was admitted to our department. Head CT scan revealed hypoplasia of corpus callosum, dilated lateral ventricles and bicoronal craniosynostosis.
Methods: Conventional cytogenetic assay and MLPA for microdeletions, subtelomeric deletions and duplications showed normal results. Subsequently we used a NGS panel for craniosynostosis.
Results: The sequence analysis revealed a heterozygous variant of uncertain significance in ZIC1 - c.1199G>T (p. Gly400Val). This sequence change replaces glycine with valine at codon 400 which disrupts the p. Gly400 amino acid residue in the ZIC1 protein. Variants that disrupt this residue are likely to be disease causing. As far as we know this variant is not present in population databases and has not been reported in the literature in individuals affected with ZIC1-related conditions.
Conclusion: A novel ZIC1 variant causing BAIDCS was discovered in a seven-month-old patient that presented with severe craniofacial dysmorphism and developmental delay.
References: N/A
Grants: N/A
Conflict of Interest: None declared.
EP12.004 Male patient with a novel missense variant in SMC3 causing severe phenotype of Cornelia de Lange syndrome Kimberly Roberts 1, Almuth Caliebe1, Malte Spielmann1;2, Inga Nagel1, Monika Kautza-Lucht1 1University Hospital Schleswig-Holstein, Campus Kiel, Institute of Human Genetics, Kiel, Germany; 2University Hospital Schleswig-Holstein, Campus Luebeck, Institute of Human Genetics, Luebeck, GermanyBackground/Objectives: Cornelia de Lange Syndrome (CdLS) is a developmental disorder caused by different genes that affect the cohesin complex. Among those are SMC3 variants, which are rare and usually associated with mild to moderate clinical phenotypes. Here we report a 12-year-old patient with CdLS and a missense variant in SMC3.
Methods: We acquired a patient’s family history and clinical data. Chromosome banding analysis, array-CGH, targeted gene analysis, exome sequencing and sanger sequencing were performed using blood samples. The disease’s severity was assessed using a scoring system proposed by (1).
Results: The patient presented with typical facial features of CdLS, short stature and global developmental delay. Furthermore, he has epilepsy, strabismus, tear duct malformation, hirsutism, a complete atrioventricular canal defect, gastroesophageal reflux, inguinal hernias, hypospadias and cryptorchidism. An inherited duplication of chromosome region 5q14.1 was detected using array-CGH, classified as likely benign. Exome sequencing showed a likely pathogenic heterozygous missense mutation in SMC3 (c.3442G>T, p.Ala1148Ser), confirming the clinical diagnosis of CdLS. The disease’s severity was classified as severe. A segregation analysis is pending.
Conclusion: Our patient presents with CdLS caused by a novel missense SMC3 variant. Whereas most previous case reports of CdLS with SMC3 variants describe mild to moderate phenotypes, this patient shows a severe phenotype. Our case report emphasizes the genetic heterogeneity and the variability of the phenotype of CdLS.
References: (1) Kline AD, Krantz ID, Sommer A, Kliewer M, Jackson LG, FitzPatrick DR, Levin AV, Selicorni A.; Am J Med Genet A. 143A(12):1287-96 (2007); https://doi.org/10.1002/ajmg.a.31757.
Grants: None.
Conflict of Interest: None declared.
EP12.005 Genotypic and phenotypic characterization of Romanian patients with KMT2D-related disorders VASILICA PLAIASU 1, Diana Ozunu2, Gabriela Motei2, Mihaela Ivan1, Lucica Ghita3, Carmen Trutescu4 1INSMC Alessandrescu-Rusescu, Clinical Genetics, Bucharest, Romania; 2INSMC Alessandrescu-Rusescu, Genetics Laboratory, Bucharest, Romania; 3INSMC Alessandrescu-Rusescu, Neurology Department, Bucharest, Romania; 4INSMC Alessandrescu-Rusescu, Psychiatry Department, Bucharest, RomaniaBackground/Objectives: Kabuki Syndrome (KS) is a rare disorder of epigenetic dysregulation due to some defects of histone methylation. The incidence of KS is about 1/32,000 of live births. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult and that are often mistaken for other diagnostic problems. Kabuki syndrome follows two specific inheritance patterns: KMT2D-related KS is inherited in an autosomal dominant manner and KDM6A-related KS is inherited in an X-linked manner.
Methods: We report 4 unrelated cases referred to the Genetics Department for clinical diagnosis. The patients presented with physical abnormalities (three of them with high suspicion of Kabuki phenotype), prenatal history of polyhidramnios, other medical conditions, skeletal findings, neurodevelopmental and behavioral problems. Next generation sequencing was performed and identified heterozygous mutations in KMT2D gene: c.5138_5146delinsCCTGC, c.15641G>A, c.12039_12046del, c.7228C>T, also confirmed by Sanger sequencing.
Results: An accurate phenotypical observation of certain dysmorphic features, although subtle, can direct to KS diagnosis. Pathogenic variants in KMT2D and KDM6A genes account for 70% of individuals with clinical diagnosis of Kabuki syndrome. The Kabuki molecular genetic panel (KMT2D, KDM6A) may be appropriate for confirmation of a clinical diagnosis or to establish a diagnosis in an individual with suspected Kabuki syndrome. But in case of complex phenotype with additional unspecific features is indicated a comprehensive genetic approach based on NGS technologies.
Conclusion: Early detection is essential. Genetic testing can provide an accurate diagnosis, which may help guide medical management and surveillance decisions, predict disease progression and outcome, and indicate the recurrence risk.
References:
Grants:
Conflict of Interest: None declared.
EP12.006 The burden of congenital anomaliesEvelina Marija Vatėnienė1, Algirdas Utkus1 1Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, LithuaniaBackground/Objectives: Congenital anomalies are rare individually, however according to EUROCAT, about 2.6 percent of newborns in Europe are born with one or more anomalies. Major anomalies increase infant morbidity, being the leading cause of death and hospitalization.
Methods: We present an overview of the economic impact of congenital anomalies.
Results: Over the last few decades, progress in medical care led to increased survival of these patients. They require various medical interventions and often face life-long disability. It has been established that costs related to the treatment of congenital anomalies are disproportionately high. Waitzman, N. J. et al. estimated that total medical costs for patients with spina bifida were 235,839 USD. However, direct non-medical and indirect costs were valued at 399,924 USD, exceeding direct medical costs. Decreased life expectancy, lost work capacity, need for special education, caregiver time cost, and other factors have a more significant economic burden than medical care. Given the scale of the economic and societal impact, not enough studies have so far researched the overall burden of congenital anomalies. More research should be focused on prevention possibilities to reduce this impact. It is known that many congenital anomalies are linked to genetic causes. Current advances in genetic testing allow better risk assessment and offer various diagnostic options before and during pregnancy. However, further understanding of the genetic role is necessary to improve existing preventive measures.
Conclusion: Total burden of congenital anomalies remains undervalued. Researching the causes and prevention together with timely genetic counselling and testing could significantly reduce the overall cost.
References:
Grants:
Conflict of Interest: None declared.
EP12.007 A case of Cat Eye Syndrome (CES) and mosaic additional dic(15;22) marker chromosome Piret Mertsina 1, Piret Ilisson1, Ave Auser1, Kati Kuuse1, Gita Taurina2, Gunta Kalnberza3, Zane Enina3, Agnese Berzina3, Katrin Ounap1;4 1Tartu University Hospital, United Laboratories, Department of Clinical Genetics, Tartu, Estonia; 2Children’s University Clinical Hospital, Clinic for Medical Genetics and Prenatal Diagnostics, Riga, Latvia; 3Children’s University Clinical Hospital, Laboratory, Riga, Latvia; 4University of Tartu, Institute of Clinical Medicine, Tartu, EstoniaBackground/Objectives: Cat eye syndrome is chromosomal disorder mainly associated with the bisatellited supernumerary chromosome, inv dup(22). Cat eye syndrome critical region in chromosome 22 is multiplied causing partial trisomy or tetrasomy of region 22q11. Mosaicism is described in 1/3 of cases. CES phenotype varies largely resulting from mild to severe malformations affecting multiple organs – eye (chorioretinal coloboma), anus (atresia), ears (preauricular pit or tag), heart and/or kidney (malformations). Mild to moderate intellectual disability is described.
Methods: We report a case of CES in female newborn with congenital tetralogy of Fallot and one tiny preauricular tag. The phenotype is associated with additional dicentric marker chromosome derived from chromosome 15 and 22 centromeric regions.
Results: First chromosomal microarray analysis revealed a pathogenic copy number gain of chromosome 22 region 22q11.1-q11.21 (2,2Mb) containing of CES causing genes and benign gain of chromosome 15 centromeric region 15q11.1-q11.2 (2,7 Mb). Karyotype from blood showed one to two additional marker chromosomes in mosaic form – 48,XX,+mar1x2[14]/47,XX,+mar1[12]/46,XX[4]. FISH analysis with chromosome 15 centromeric probe showed signal on both markers. Additional FISH analysis with chromosome 14/22 centromeric probe showed an additional signal on both markers.
Conclusion: The patient has one to two extra marker chromosomes, dicentric and bisatellited, containing 15pter-q11.2 and 22pter-q11.21 material. The multiplied region of 22q11.21 is causative for CES. The patient’s final karyotype is: mos 48,XX,+dic(15;22)(q11.2;q11.21)x2 dn/47,XX,+dic(15;22)/46,XX.ish dic(15;22)(D15Z4+,D22Z1+). To our knowledge the dicentric marker of chromosomes 15 and 22 associated with CES has not been described before.
References:
Grants: Estonian Research Council grant PRG471.
Conflict of Interest: Piret Mertsina: None declared, Piret Ilisson: None declared, Ave Auser: None declared, Kati Kuuse: None declared, Gita Taurina: None declared, Gunta Kalnberza: None declared, Zane Enina: None declared, Agnese Berzina: None declared, Katrin Ounap part-time, Estonian Research Council grant PRG471.
EP12.008 CEDNIK syndrome in a Brazilian patient with compound heterozygous pathogenic variants Natalia Nunes 1, Malú Zamariolli1, Anelisa Gollo Dantas1, Paula Cristina Cola2, Francisco Agostinho2, Flavia Balbo Piazzon1;3, Vera Ayres Meloni1;2, Maria Isabel Melaragno1 1Genetics Division, Department of Morphology and Genetics - Universidade Federal de São Paulo, São Paulo, Brazil; 2Marília University (UNIMAR), Medicine Department, Marília, São Paulo, Brazil; 3University of Liège, Belgium, Division of Child Neurology, Department of Pediatrics, CHR, Liège, BelgiumBackground/Objectives: CEDNIK (Cerebral Dysgenesis, Neuropathy, Ichthyosis, and Keratoderma) syndrome is a neuro ichthyotic syndrome characterized by a clinical constellation of features including severe developmental delay, microcephaly, and facial dysmorphism with autosomal recessive pattern (Sprecher E et al; 2005). Here, we report a characterization of a Brazilian patient with CEDNIK syndrome harbouring two compound heterozygous variants in the SNAP29 gene.
Methods: Whole-exome sequencing was performed with Illumina platform and revealed two genetic variants affecting SNAP29 gene. To validate the findings, it was performed chromosomal microarray (CytoScan HD, Affymetrix) and Sanger sequencing on peripheral blood DNA from the patient. Parental inheritance of the variants was investigated on peripheral blood.
Results: We identified compound heterozygous mutations in the SNAP29 gene (NP_004773.1:p.Leu119fs and arr[GRCh37] 22q11.21(21033398_21798907)×1). The father was a carrier of the NP_004773.1:p.Leu119fs variant, and in the mother, SNP-array showed an interstitial deletion at 22q11.2, with similar breakpoints to the proband’s (arr[GRCh37] 22q11.21(21033398 21798907)×1), indicating a maternal inheritance of the deletion.
Conclusion: This report provides a patient with unprecedented genetic events leading to the CEDNIK phenotype and may contribute to accumulating research regarding this rare clinical condition.
References: Sprecher E et al; (2005); A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma. Am J Hum Genet 77: 242-51. https://doi.org/10.1086/432556.
Grants: FAPESP (grant #2019/21644-0), CAPES, and Projeto Amor de Criança, Marília University, São Paulo, Brazil.
Conflict of Interest: None declared.
EP12.009 Minimal critical region and genes for a typical presentation of Langer-Giedion SyndromeBianca Pereira Favilla1, Bruna Burssed1, Érika Mitie Yamashiro Coelho1, Ana Beatriz Alvarez Perez1, Maria de Fátima de Faria Soares1, Vera Ayres Meloni1, Fernanda Teixeira Bellucco1, Maria Isabel Melaragno 1 1Universidade Federal de São Paulo, São Paulo, BrazilBackground/Objectives: Langer-Giedion Syndrome (LGS) is caused by a contiguous gene deletion at 8q23-q24. The syndrome is characterized by multiple exostoses, facial, ectodermal, and skeletal anomalies, and, in some cases, intellectual disability. Patients with LGS have been diagnosed clinically or by routine cytogenetic techniques, thus hampering the definition of an accurate genotype-phenotype correlation for the syndrome.
Methods: We characterized two unrelated patients with deletions involving chromosome 8q through cytogenomic techniques, assessed the pathogenicity of the genes within our patients’ deleted segments, and reviewed other molecularly confirmed cases described in the literature.
Results: We identified deletions in the 8q23-q24 region in both patients with one of them, to the best of our knowledge, being the smallest deletion reported in classic LGS cases. Thus, our findings suggest a 3.2 Mb minimal critical region for a typical presentation of the syndrome, emphasizing the contribution of the TRPS1, RAD21, and EXT1 genes’ haploinsufficiency in establishing its most common features, including bone dysplasia, intellectual disability, and exostoses, respectively. Additionally, we identified a possible role for the CSMD3 gene, whose deletion could contribute to other uncommon phenotypic characteristics, such as central nervous system anomalies.
Conclusion: Since studies performing this correlation for LGS patients are still limited, our data contribute to improving the genotype-phenotype characterization for patients with LGS.
References:
Grants: CAPES, FAPESP, Brazil.
Conflict of Interest: Bianca Pereira Favilla: None declared, Bruna Burssed: None declared, Érika Mitie Yamashiro Coelho: None declared, Ana Beatriz Alvarez Perez: None declared, Maria de Fátima de Faria Soares: None declared, Vera Ayres Meloni: None declared, Fernanda Teixeira Bellucco: None declared, Maria Isabel Melaragno FAPESP 2019/21644-0.
EP12.010 A maternal inherited rare case with chromoanagenesis-related complex chromosomal rearrangements and de novo microdeletionsJui-Hung Yen1, Yi-Chieh Su2, Yen-Shian Lee2, Chun-Ching Chien2, Chun-Ying Weng2, Shao-Yin Chu2;3, Pei-Yi Chen 1;2 1Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan; 2Center of Medical Genetics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; 3Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, TaiwanBackground/Objectives: Complex chromosomal rearrangements (CCR) are structural rearrangements involving three or more chromosomal breaks and exchange of genetic materials between at least two chromosomes. We here present a 3 years-old boy exhibiting multiple congenital malformations and developmental delay. Cytogenomic techniques identify the proband has a maternal-inherited CCR with the features of chromoanagenesis, a phenomena of massive and chaotic shattering and restructuring of chromosomes.
Methods: Karyotyping, fluorescent in situ hybridization (FISH), spectral karyotyping (SKY) and microarray were performed to characterize the genomic aberrations by the proband’s and parental bloods.
Results: The proband presented with speech delay, psychomotor retardation and facial dysmorphism. Cytogenetic analysis found a highly complex chromosomal rearrangements involving four chromosomes (2, 3, 6 and 11), 5 breakpoints as a result of one deletion, one insertion, and three translocations forming three derivative chromosomes. FISH and SKY identified a chromoanagenesis-related derivative chromosome 11 contained three parts connecting the intact 11q telomere to partial 6q and 3q fragments. Microarray studies further revealed one submicroscopic deletion at 6p12.1 (626 kb) inherited from the mother, and two additional de novo deletions at 6q14.1 (914 kb) and 6q16.1~6q16.3 (2.1 Mb), respectively.
Conclusion: We report one maternal inherited CCR with congenital anomalies and the use of cytogenomic techniques to characterize the genomic alterations. FISH and SKY revealed one derivative chromosome 11 linked 11q telomere with 6q and 3q fragments. Microarray identified two de novo microdeletions at 6q. We suggest that chromoanagenesis could be a possible mechanism involved in the repair and restructuring of these rearrangements.
References:
Grants:
Conflict of Interest: None declared.
EP12.011 Clinical and cytogenetic correlation in a case of tetrasomy 9p syndrome Morana Miklos 1, Anita Pokupec Bilic1, Ivana Tonkovic Djurisevic1, Kristina Crkvenac Gornik1, Sanda Huljev Frkovic2 1University Hospital Center Zagreb, Department of Laboratory Diagnostics, Zagreb, Croatia; 2University Hospital Center Zagreb, Department of Pediatrics, Zagreb, CroatiaBackground/Objectives: Tetrasomy 9p is a rare chromosomal disorder, characterized by the presence of a supernumerary chromosome, containing two short arms of chromosome 9. It could be present in all cells or in some of them in a form of mosaicism.
A patient (newborn) was the first child of unrelated healthy parents. During mother’s pregnancy, NIPD test indicated duplication of the region 9p24-p13.1, confirmed using amniocentesis. Fetal ultrasound scan showed intrauterine growth retardation and multiple congenital anomalies. Newborn had facial dysmorphia (hypertelorism, cleft lip and palate, microretrognathia, poorly formed and low set ears), short neck, hypoplastic digits and nails, partial syndactyly, widely spaced cranial sutures, partial corpus callosum agenesis, multiple heart defects and underdeveloped genitalia.
Methods: Cytogenetic and FISH analysis were used for samples of peripheral blood and buccal smear.
Results: Karyotype 47,XY,+psu idic(9)(pter→q12::q12→pter) was confirmed in 100% lymphocytes and 71,4% buccal smear cells.
Conclusion: Clinical symptoms of tetrasomy 9p vary from multiple malformations, developmental and intelectual dissorders to normal fenotype and high intelectual level. It is assumed that tetrasomy 9p in fibroblasts leeds to more severe symptoms than the one limited only to lymphocytes. Because of a variety of clinical symptoms, more cases of tetrasomy 9p in different tissues should be described.
References: I. Papoulidis, M. Kontodiou, M. Tzimina, I. Saitis, A.B. Hamid, E. Klein, N. Kosyakova, U. Kordaß, J. Kunz, E. Siomou, P. Nicolaides, S. Orru, L. Thomaidis, T. Liehr, M.B. Petersen, E. Manolakos: Tetrasomy 9p Mosaicism Associated with a Normal Phenotype in Two Cases. Cytogenet Genome Res 2012;136:237–24.
Grants:
Conflict of Interest: None declared.
EP12.012 Case Report: Compound Heterozygous COL3A1 Variants in a Child with Brain Anomalies including Polymicrogyria and Heterotopia Chayim Schell-Apacik 1, Teresa Neuhann2, Heinz Gabriel3 1Schell Genetics, London, United Kingdom; 2MGZ - Medical Genetics Center, Munich, Germany; 3Praxis fuer Humangenetik Tuebingen, Tuebingen, GermanyBackground/Objectives: Homozygous or compound heterozygous variants in the COL3A1 gene can cause Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (PMGEDSV – OMIM #618343), a very rare autosomal recessive disorder with a highly variable phenotype.
Methods: Here we report on a 7-month-old developmentally delayed boy who presented with a broad, high and prominent forehead, widely spaced eyes, a thin upper lip and translucent skin. He was delivered by emergency C-section in the 36th gestation week due to severe fetal tachycardia in CTG. He had persisting supraventricular tachycardia until day 5 which ceased after medication. Echocardiography revealed a small pericardial effusion and a tachycardia-induced cardiomyopathy. Brain MRI performed at the age of 4 months showed extensive bilateral frontal and parietal migration disorder mainly polymicrogyria as well as multiple subcortical heterotopias in the occipital region, a thin corpus callosum and symmetrically dilated ventricles.
Results: Investigations showed that the child carries two pathogenic COL3A1 gene variants (heterozygous variant c.1744G>A; p.Gly582Ser and heterozygous variant c.2338-2A>G; p.?) inherited from either parent.
Conclusion: The child’s clinical presentation was in keeping with previous reports of patients with PMGEDSV even though a severe supraventricular tachycardia has not been described previously. Whereas heterozygous variants in the COL3A1 gene may cause the vascular type of Ehlers-Danlos syndrome (EDSVASC – OMIM #130050), either parent displayed only very subtle features with no vascular involvement.
References: OMIM #618343, OMIM #130050.
Grants:
Conflict of Interest: None declared.
EP12.013 Clinical and radiological aspects of 34 Brazilian individuals with oculoauriculofrontonasal syndrome: diagnostic implications Henrique Serigatto 1, Nancy Kokitsu-Nakata1, Siulan Vendramini-Pittoli1, Priscila Moura1, Cristiano Tonello2, Adriano Peixoto3, Roseli Zechi-Ceide1 1Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Clinical Genetics and Molecular Biology, Bauru, São Paulo, Brazil; 2Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Craniomaxillofacial Surgery, Bauru, São Paulo, Brazil; 3Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Orthodontics, Bauru, São Paulo, BrazilBackground/Objectives: Oculoauriculofrontonasal syndrome (OAFNS) is a rare condition, with unknown aetiology, characterised by the clinical association of oculoauriculovertebral spectrum and frontonasal dysplasia features. Here we report a Brazilian cohort with 34 affected individuals and describe the most frequent clinical findings.
Methods: Individuals with clinical diagnosis of OAFNS from the Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Brazil, were included. Clinical and genetics aspects were considered.
Results: Thirty-four individuals were included in this study. Sex ratio showed male predilection (22M:12F). No recurrence and consanguinity were noted. The individuals were classified as bilateral (85,3%) and unilateral (14,7%). Main clinical features included facial asymmetry (100%), ocular hypertelorism (100%), rare craniofacial clefts (97,0%), preauricular tags (91,1%), and microtia (85,3%). Tessier cleft number 0 (72,7%), 2 (66,7%), and 7 (54,5%) were the most frequent. Complex craniofacial clefts combinations were noted in some cases. Central nervous system abnormalities were observed in 64,2% (18 out 28), mainly corpus callosum lipoma. The ectopic nasal bone was observed in 8 (40,0%) out 20 individuals evaluated through computed tomography scan. Whole exome sequencing performed in one individual was normal.
Conclusion: The phenotype is heterogeneous and variable, affecting most individuals bilaterally. There is a male predilection. Tessier cleft number 2 is an important finding in this condition. The ectopic nasal bone was frequent in our cohort, confirming this is a hallmark of OAFNS. The absence of recurrence, consanguinity, chromosomal and genetic abnormalities reinforce the hypothesis of a non-traditional inheritance model.
References:
Grants: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES).
Conflict of Interest: None declared.
EP12.014 Novel finding in a patient with 17p13.1 deletion syndrome: a case report Momen Kanjee 1, Neslihan Cinkara1, Cigdem Yuce Kahraman1, Abdulgani Tatar1 1Atatürk University Faculty of Medicine, Department of Medical Genetics, Erzurum, TurkeyBackground/Objectives: Chromosome 17p13.1 deletion syndrome (OMIM#613776) is a rare contiguous gene syndrome characterized by developmental delay, intellectual disability, absent of speech, and various dysmorphic features. This deletion size ranges from 287kb to 4.4Mb. Here, we report the first patient with 17p13.1 deletion syndrome from Turkey who has thoracic syringomyelia; a new finding that has not been reported before.
Methods: After obtaining informed consent from the family, Chromosomal Microarray Analysis (CMA) was performed using Illumina HumanCytoSNP-12 BeadChip kit, and scanned by Illumina iScan system. Results were interpreted using Illumina BlueFuse Multi software.
Results: An 8-month-old girl was referred to our clinic due to hypotonia, neuromotor developmental delay, sacral dimple, facial dysmorphism, bilateral kidney stones, and thoracic syringomyelia. CMA revealed a 1.1 Mb heterozygous deletion; arr[GRCh37] 17p13.2p13.1 (chr17:6,163,462_7,258,861) x1.
Conclusion: According to the American College of Medical Genetics and Genomics (ACMG) guidelines, CMA is recommended as a first-tier test for patients with intellectual disabilities, autism, and/or congenital anomalies. To the best of our knowledge, 17p13.1 deletion syndrome has been identified in only sixteen patients with various phenotypes, and here we reported the seventeenth patient with 17p13.1 deletion syndrome, presenting with a new finding.
References: Giordano L, Palestra F, Giuffrida MG, et al. 17p13.1 microdeletion: genetic and clinical findings in a new patient with epilepsy and comparison with literature. Am J Med Genet A. 2014;164A(1):225-230. https://doi.org/10.1002/ajmg.a.36225.
Krepischi-Santos AC, Rajan D, Temple IK, et al. Constitutional haploinsufficiency of tumor suppressor genes in mentally retarded patients with microdeletions in 17p13.1. Cytogenet Genome Res. 2009;125(1):1-7. https://doi.org/10.1159/000218743.
Grants: None.
Conflict of Interest: None declared.
EP12.015 Severe psychomotor delay and new eye findings in a child with biallelic mutations in LAMA1 gene - expanding clinical spectrum of Poretti-Bolthauser syndrome Laura Mauring 1;2;3, Eve Õiglane-Shlik4, Sander Pajusalu1;2, Tiina Kahre1;2, Katrin Ounap1;2 1Tartu University Hospital, Department of Clinical Genetics, United Laboratories, Tartu, Estonia; 2University of Tartu, Department of Clinical Genetics, Institute of Clinical Medicine, Tartu, Estonia; 3Tartu University Hospital, Eye Clinic, Tartu, Estonia; 4Tartu University Hospital, Children’s Clinic, Tartu, EstoniaBackground/Objectives: LAMA1 gene (OMIM: LAMININ, ALPHA-1; LAMA1; #150320) encodes for laminin, which is a basement membrane protein and a crucial component of the extracellular matrix. Aldinger et al. (2014) identified homozygous or compound heterozygous variants in the LAMA1 gene in patients presenting with Poretti-Bolthauser syndrome. The described patients had cerebellar dysplasia and cysts, vermis atrophy, high myopia, variable retinal dystrophy, and eye movement abnormalities. All patients had delayed motor development, and most had speech delay, whereas cognitive function was variable.
Methods: We present a case of a 3.5-year-old child with severe psychomotor developmental delay, hypotonia, intractable epilepsy, cerebral abnormalities, including agenesis of the corpus callosum, polymicrogyria and grey-matter heterotopia, colobomatous optic discs and chorioretinal colobomas. Trio exome sequencing (ES) was carried out.
Results: ES revealed two missense variants in LAMA1 gene in heterozygous state: paternally inherited NM_005559.3(LAMA1):c.7748C>T, p.(Ala2583Val) and maternally inherited NM_005559.3(LAMA1):c.554A>G, p.(Tyr185Cys). Our patient’s cerebral malformation was substantially more prevalent than cerebellar abnormalities described in the literature. She also presented with global developmental delay that has not yet been described. In addition to this, our patient did not present with high myopia but rather hypermetropia and had colobomatous findings in the fundus.
Conclusion: According to our knowledge, this is the first case published with this severe phenotype in a patient with Poretti-Bolthauser syndrome. We would like to reach out to collaborators who have expertise in this syndrome with this severe clinical presentation.
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Grants: Estonian Research Council grants PRG471, MOBTP175, PSG774.
Conflict of Interest: None declared.
EP12.016 A syndrome of severe intellectual disability, hypotonia, failure to thrive, dysmorphism and thinning of corpus callosum maps to chromosome 7q21.13-q21.3Daniel Halperin1, Nadav Agam 1, Analya Mijalovsky2, Ohad Shmuel Birk1;3 1Ben Gurion University of the Negev, The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Be’er Sheva, Israel; 2Soroka University Medical Center, Zusman Child Development Center, Division of Pediatrics, beer sheva, Israel; 3Soroka University Medical Center, Genetics Institute, beer sheva, IsraelBackground/Objectives: Seven individuals of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of severe global developmental delay, positive pyramidal signs, craniofacial dysmorphism - consisted of a triangular face with a prominent forehead and midface hypoplasia, severe failure to thrive with normal birth weights, and over-riding toes, with clinodactyly or syndactyly. Magnetic resonance imaging demonstrated thinning of the corpus callosum and paucity of white matter. Early-onset axial hypotonia evolved with progressive muscle weakness, reduced muscle tone, and hyporeflexia.
Methods: Genome-wide linkage analysis was carried using single nucleotide polymorphism arrays for nineteen family members (bead chips) and the HomozigosityMapper and SuperLink softwares (1, 2). Whole-exome-and-genome sequencing was performed for three individuals (arrow heads) and analysed using the Qiagen Clinical Insight software and our in-house database of ~700 samples.
Results: A single ~4 Mbp disease-associated locus was identified on chromosome 7, between rs6952664 and rs13234589 (maximal LOD score of 5.01). Next generation sequencing analysis identified no non-synonymous pathogenic biallelic variants within this locus. Notably, no variants were found in any of the genes previously associated with cases of Russell-silver, Seckel, or Zellweger syndromes.
Conclusion: Considering the consanguinity of the kindred and the homozygosity locus shared by the affected individuals, recessive heredity is the most likely, although other forms of monogenic heredity, such as genomic imprinting, cannot be entirely ruled out. Following the exclusion of partially resembling syndromes, we now describe a novel autosomal recessive syndrome mapped to a ~4Mbp locus on chromosome 7.
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Grants: The Morris Kahn Family Foundation.
Conflict of Interest: None declared.
EP12.017 Clinical or whole exome sequencing for mutation analysis in families with rare genetic syndromes? Helena Paszeková 1, Lucie Hrušková1, Tomáš Píš1, Zděnka Vlčková1, Renáta Michalovská1 1GHC Genetics, Prague, Czech RepublicBackground/Objectives: During the last two years we have sequenced and analyzed over 150 patients with various clinical features and suspect diagnoses, including those of rare genetic syndromes.
Methods: We performed massive parallel sequencing of gDNA isolated from whole blood on NextSeq550 using panel Clinical Exome Solutions (CES v2) and Whole Exome Solutions (WES v2) by Sophia Genetics. CES v2 covers the coding regions (± 5bp of intronic regions) of 4,490 genes related to rare and inherited diseases. WES v2 covers 19,425 nuclear genes and the full mitochondrial genome. SOPHiA DDM™ platform analyses complex genomic NGS data by detecting, annotating and pre-classifying genomic variants and includes trio analyses approach with variant analysis inheritance mode.
Results: Using molecular genetic analysis, we have identified previously unreported de novo variants in trio analyses in families with rare syndromes, that could not be found by CES v2. In 3-year old boy with psychomotor retardation we reported de novo frameshift heterozygous variant c.3943dupA in SON gene. SON gene is associated with ZTTK syndrome, that is characterized by mental retardation, malformations and developmental delay. A 19-year old woman with suspected Wiedermann-Steiner syndrome was proven to bear de novo frameshift heterozygous variant c.126delC in KMT2A gene, a causative gene in Wiedermann-Steiner syndrome.
Conclusion: Performing WES in trio analyses with no causative variant found by CES demonstrates the role of WES in molecular diagnostics for families with rare syndromes caused by de novo and previously unreported mutations.
References:
Grants:
Conflict of Interest: Helena Paszeková researcher, Lucie Hrušková researcher, Tomáš Píš researcher, Zděnka Vlčková head of genetics, Renáta Michalovská head of laboratory.
EP12.018 Copy number variations identified using whole-genome sequencing as genetic markers for pediatrics patients with developmental defects Jiahong Sun 1, Chien-Ling Huang1, Ho Ming Luk2, Fei Meng1, Fai Man Lo2, Shea Ping Yip1 1The Hong Kong Polytechnic University, Department of Health Technology and Informatics, Hong Kong, China; 2Clinical Genetic Service, Department of Health, Hong Kong, ChinaBackground/Objectives: Whole-genome sequencing (WGS) has been widely applied in studying the genetic causes, such as copy number variations (CNVs), for both rare and complex diseases. However, its clinical applications are limited due to the high false positive detection rate. Despite many bioinformatics tools have been developed to identify the CNVs for WGS data, a stable and reliable approach for CNV calling in clinical samples is still pending.
Methods: We systematically evaluated several CNV calling methods and investigated the effects of sequencing depth and detection resolution in CNV calling by using synthetic data. We built a pipeline with the best performance by integrating the results from different methods. Then we applied the optimized pipeline to WGS data from 88 pediatric patients with developmental defects to discover potential pathogenic CNVs. Validation experiments were performed to assess the findings.
Results: Our newly constructed pipeline (integration of GATK_gCNV, LUMPY, DELLY, cn.MOPS and CNVKit) gave the highest sensitivity and lowest false discovery rate for 10x-depth sequencing data under 5k resolution. For patient data analysis, we not only found many CNVs that were reported to be associated with developmental defects but also identified several novel pathogenic CNVs and genes that might contribute to the diseases. In addition, some mutated genes were enriched in the pathway of immune response.
Conclusion: We developed a CNV calling pipeline for whole-genome sequencing data of clinical samples. This method helped identify novel pathogenic CNVs for pediatric patients with developmental defects.
References:
Grants: This study was funded by Health and Medical Research Fund (no. 16172331 to C.L.H).
Conflict of Interest: None declared.
EP12.019 Extensive deletion of 22q12 in a patient with bilateral schwannoma, mental retardation, sensorineural hearing loss and epilepsy: case report Zuzana Vrzalova 1;2, Jakub Trizuljak1;2;3, Jakub Duben3, Ivona Blahakova1;2, Katerina Stano Kozubik1;2, Jiri Stika1, Sona Mejstrikova1;2, Sarka Pospisilova1;2;3, Michael Doubek1;2;3 1Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 2Department of Internal Medicine - Hematology and Oncology, University Hospital Brno, Brno, Czech Republic; 3Department of Medical Genetics and Genomics, Masaryk University, Brno, Czech RepublicBackground/Objectives: In contrast with the well-known and described deletion of the 22q11 chromosome region responsible for DiGeorge syndrome, 22q12 deletions are much rarer. However, this region contains genes responsible for cell cycle control, chromatin modification, transmembrane signaling, cell adhesion and neural development. We present a 25-years old man with cleft palate, sensorineural hearing loss, vestibular dysfunction, epilepsy, mild to moderate mental retardation, divergent strabism, pes equinovarus, platyspondylia, and bilateral Schwannoma.
Methods: NGS testing for cancer susceptibility genes, MLPA analysis and Microarray-based Comparative Genomic Hybridization (array-CGH) was performed.
Results: CNV analysis of the sequencing data discovered a heterozygous loss of all exons of CHEK2 tumor suppressor gene, as well as heterozygous loss of the neurofibromin 2 (NF2) gene. The MLPA analysis confirmed the presence of NF2 deletion. Finally, array-CGH determined an extensive, 3.8Mb sized, 22q12.1-22q12.3 heterozygous deletion, including the CHEK2 and NF2 regions. The interstitial deletion was not detected in either parent, so de novo origin of the deletion was presumed.
Conclusion: In this article, we focus on the clinical presentation, individual characteristics of the proband and comparison to previously reported cases with similar large deletions.
References:
Grants: Supported by the Ministry of Health of the Czech Republic (under Grant NU20-08-00137); Masaryk University (grant MUNI/A/1330/2021) and the European Regional Development Fund-Project „A-C-G-T“ (under Grant CZ.02.1.01/0.0/0.0/16_026/0008448).
Conflict of Interest: None declared.
EP12.020 Expanding the phenotypic picture of Witteveen-Kolk syndrome: the first Hungarian case András Szabó 1, Márta Czakó2, Agnes Till2, Anna Zsigmond2, Kinga Hadzsiev2 1University of Pécs, Clinical Centre, Department of Medical Genetics, Pécs, Hungary; 1University of Pécs, Clinical Centre, Department of Medical Genetics, Pécs, HungaryBackground/Objectives: Witteveen–Kolk syndrome (WITKOS) is an extremely rare genetic disorder mainly characterized by mild to moderate intellectual disability, global developmental delay, and dysmorphic facial features, occasionally supplemented with skeletal abnormalities, microcephaly, malformation of the brain, ectodermal symptoms, and ophthalmic abnormalities. Haploinsufficiency of SIN3A is responsible for this syndrome. The transcriptional repressor protein encoded by SIN3A plays a regulatory role of cortical expansion and maturation. To date, only 18 patients with WITKOS have been reported in the medical literature including 11 patients with mutations in the SIN3A and seven patients having microdeletions encompassing SIN3A. Hereby, we report the first Hungarian patient with WITKOS presenting pronounced lower limb hypertrophy and high arched feet as additional findings, supplementing the previously described clinical picture.
Methods: Array comparative genomic hybridization (aCGH) was applied for the investigation of a Hungarian boy with intellectual disability, global developmental delay and minor anomalies using Agilent SurePrint G3 Human CGH Microarray 8x60K oligo-array.
Results: aCGH examination of the patient revealed a 1.415 Mb (74419546_75834623) copy number loss of the 15q24.1q24.2 chromosomal region. The affected chromosomal region contains several genes including SIN3A, responsible for the development of WITKOS.
Conclusion: We report the first Hungarian patient with WITKOS harbouring a novel 15q24.1q24.2 deletion including SIN3A presenting psychomotor delay, minor anomalies supplemented with lower limb hypertrophy and high arched feet, which have not been described so far. This report contributes to the expansion of the phenotypic picture of WITKOS, and highlights the importance of detailed phenotyping and application of aCGH in the investigation of such patients.
References:
Grants:
Conflict of Interest: None declared.
EP12.021 Axenfeld-Rieger anomaly masking a myopathy Ehlers‐Danlos syndrome in a family segregating FOXC1 and COL12A1 mutations Daniela Pencheva 1, Kunka Kamenarova1, Kalina Mihova1, Darina Kachakova-Yordanova1, Nevyana Veleva2, Radka Kaneva1 1Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University - Sofia, Sofia, Bulgaria; 2Department of Ophthalmology, University Hospital Alexandrovska, Medical University - Sofia, Sofia, BulgariaBackground/Objectives: Axenfeld-Rieger syndrome (ARS) is a disorder affecting the anterior segment of the eye and causing systemic malformations, and follows an autosomal-dominant inheritance pattern. Pathogenic variants in COL12A1 cause a rare form of congenital connective tissue/myopathy overlap syndrome subsumed under the classification of “myopathic Ehlers‐Danlos syndrome (EDS)”. The aim of the present study was to identify the genetic cause of complex phenotype in a pedigree affected by ARS.
Methods: A Bulgarian family presented with an autosomal-dominant inheritance pattern for ARS that affected mother and the two children was recruited. Targeted sequencing of clinical exome of the affected daughter was performed on MiSeq platform of Illumina, followed by Sanger sequencing for segregation analysis. CNVs identified by next-generation sequencing were confirmed by MLPA.
Results: A heterozygous deletion of the only exon of the forkhead box C1, FOXC1, gene was detected and then confirmed by MLPA in all affected family members. A novel missense variant, c.4166C>G (p.Ser1389Cys), that was classified as likely pathogenic according to ACMG criteria was found in the gene coding collagen type XII alpha-1, COL12A1. Both mutations were not present in the healthy father.
Conclusion: Our results demonstrate that a novel mutation in COL12A1 and a known exon 1 deletion of FOXC1 co-segregates with two autosomal-dominant clinically overlapping syndromes – AR anomaly and myopathic EDS, respectively. Therefore, molecular-genetic analysis is of emerging importance for clinically diagnostic and genetic counseling of overlapping complex diseases.
References: OMIM (https://www.omim.org/).
Grants: D01-285/17.12.2019, D01-395/18.12.2020, D01-302/17.12.2021.
Conflict of Interest: None declared.
EP12.022 A new case of Perching syndrome detected by WES in a patient with severe failure to thrive, dysmorphic features and LOH of 7p21p14.33 Václava Curtisová 1;2, Radek Vrtěl1;2, Patrícia Žižkovičová2;3 1University Hospital Olomouc, Olomouc, Czech Republic; 2Palacký University Olomouc, Olomouc, Czech Republic; 3Institute of Molecular and Translational Medicine, Olomouc, Czech RepublicBackground/Objectives: Perching syndrome is a rare autosomal recessive condition characterised by global developmental delay, dysmorphic features, feeding and respiratory difficulties, poor overall growth, axial hypotonia, and joint contractures. We present a newly diagnosed patient with clinical signs of Perching syndrome and a previously unreported homozygous pathogenic variant in KLHL7 gene.
Methods: The patient was examined as a neonate for polyhydramnios, growth restriction and dysmorphic features. Repeated consultations at the age of 5m, 20m and 4yr8m revealed severe failure to thrive, feeding difficulties and vomiting requiring PEG, developmental delay, frequent infections, febrile convulsions, excessive sweating, episodes of raised temperature, bilateral inguinal hernias, undescended testes, and dilatation of the frontal horns of lateral ventricles. Dysmorphic features included triangular face, hypertelorism, proptosis, wide nasal bridge, arched palate, low set ears, overlapping fingers and toes, single palmar creases.
Results: Karyotype was 46,XY, SNPaCGH revealed LOH in 7p21p14.33. WES detected a homozygous frame shift variant KLHL7(NM_001031710.3): c.969del (p.Phe323LeufsTer15) in a highly conserved area of the gene not found in gnomAD.
Conclusion: Our report helps to further delineate the phenotype of patients with biallelic variants in KLHL7 gene. It also presents previously unreported variant in KLHL7 gene. Homozygosity of the variant was caused by a loss of heterozygosity of the critical region of chromosome 7 in unrelated parents. The diagnosis was only reached due to the results of WES, which highlights the usefulness of the method in diagnostics of rare syndromes.
References:
Grants: MH CZ – DRO (FNOL, 00098892), BBMRI-CZ: LM2018125.
Conflict of Interest: None declared.
EP12.023 Paternal occupational exposures to endocrine disruptors and the risk of congenital malformations using job-exposure matrixNouha ABDELMOULA1, Ali Lamine1, Balkiss Abdelmoula
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